Biology subjects

Kalapala, Y. C.

Publications and source records attributed to Kalapala, Y. C..

3 recordsLinked to original sources

bioRxiv2026

Dissolution-Controlled Nanocrystalline Rifapentine Formulation for Tuberculosis Treatment

Current tuberculosis (TB) treatment suffers from drawbacks such as long regimens, high pill burden and side effects leading to non-adherence and poor treatment outcomes. Dissolution-controlled drug depot formulation with high drug loading is a clinically successful drug delivery strategy. Such depots reduce the dosing frequency for treatments requiring daily administration, thereby improving treatment adherence and compliance. However, dissolution-controlled depots for first-line TB drugs have not been demonstrated due to their high solubility and high dose requirements. In this study, we overcame this challenge by developing injectable, extended-release, dissolution-controlled depots of nanocrystalline rifapentine (NCRPT), microcrystalline rifapentine (MCRPT) and amorphous rifapentine microparticles (ARPT) with more than 75% loading. Crystalline formulations resulted in much slower depot dissolution compared to amorphous formulations. A single intramuscular (IM) injection of NCRPT in mice resulted in therapeutic serum concentrations for over a week. We then demonstrated the efficacy of NCRPT in both pre-exposure prophylaxis and therapeutic models of mice TB. NCRPT administered at 60 mg/kg once every two weeks demonstrated excellent efficacy in a mouse model of TB infection. In each case, a [~] 4-log-fold reduction in lung bacterial load compared to untreated mice was observed. These results open new avenues for developing LAI formulations of TB drugs and could improve patient compliance and TB management.

bioengineering↗

bioRxiv2026

Bacteriophage utilize pseudolysogeny to target non-replicating bacteria and CRISPR-resistant phages eliminate recalcitrant implant infections

A key driver of bacterial infection treatment failure and relapse is the persistence of non-replicating bacterial subpopulations that emerge under stressors like nutrient starvation and immune pressure. These dormant cells evade antibiotics, fuelling recurrence and resistance. Bacteriophage therapy is a promising alternative, but its efficacy against non-replicating bacteria is poorly understood. Improving our understanding of bacteria-phage interactions under non-replicating conditions could greatly enhance phage therapeutic outcomes in clinics. By utilising various bacterial (Mycobacterium smegmatis, Mycobacterium tuberculosis, and Pseudomonas aeruginosa) and phage species, this study quantitatively demonstrates that lytic phages can infect non-replicating bacteria (under nutrient starvation, acidic pH or antibiotic pressure), persisting in a state of pseudolysogeny and resuming lysis upon bacterial regrowth. We find that the pseudolysogeny window is phage- and host-dependent, with degradation of extrachromosomal phage DNA leading to loss of pseudolysogeny. We find that Pseudomonas CRISPR defence plays a crucial role in phage DNA degradation even under non-replicating conditions, underscoring the need for its consideration in phage therapy design. We also demonstrated the in vivo relevance of pseudolysogeny and CRISPR-resistant bacteriophages in eliminating implant-associated and antibiotic-persistent Pseudomonas infections in mice. These findings highlight the need to consider phage-host dynamics and bacterial defences when designing phage-based strategies to target non-replicating bacteria and persistent infections.

microbiology↗

bioRxiv2020

Antimycobacterial potential of Mycobacteriophage under pathophysiological conditions

Antibiotic resistance continues to be a major global health risk with an increase in multi-drug resistant infections seen across nearly all bacterial diseases. Mycobacterial infections such as Tuberculosis (TB) and Non-Tuberculosis infections have seen a significant increase in the incidence of multi-drug resistant and extensively drug-resistant infections. With this increase in drug-resistant Mycobacteria, mycobacteriophage therapy offers a promising alternative. However, a comprehensive study on the infection dynamics of mycobacteriophage against their host bacteria and the evolution of bacteriophage (phage) resistance in the bacteria remains elusive. We aim to study the infection dynamics of a phage cocktail against Mycobacteria under various pathophysiological conditions such as low pH, low growth rate and hypoxia. We show that mycobacteriophages are effective against M. smegmatis under various conditions and the phage cocktail prevents emergence of resistance for long durations. Although the phages are able to amplify after infection, the initial multiplicity of infection plays an important role in reducing the bacterial growth and prolonging efficacy. Mycobacteriophages are effective against antibiotic-resistant strains of Mycobacterium and show synergy with antibiotics such as rifampicin and isoniazid. Finally, we also show that mycobacteriophages are efficient against M. tuberculosis both under lag and log phase for several weeks. These findings have important implications for developing phage therapy for Mycobacterium.

microbiology↗